rs876660966
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):āc.1106A>Cā(p.Asn369Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N369K) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1106A>C | p.Asn369Thr | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1106A>C | p.Asn369Thr | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249768Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135434
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461376Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726976
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2023 | The p.N369T variant (also known as c.1106A>C), located in coding exon 9 of the BRCA2 gene, results from an A to C substitution at nucleotide position 1106. The asparagine at codon 369 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 23, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces asparagine with threonine at codon 369 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/249768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 26, 2015 | This variant is denoted BRCA2 c.1106A>C at the cDNA level, p.Asn369Thr (N369T) at the protein level, and results in the change of an Asparagine to a Threonine (AAT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 1334A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn369Thr was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn369Thr occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn369Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 234275). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 369 of the BRCA2 protein (p.Asn369Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at